PD-1信号通路在非小细胞肺癌中的研究进展

免疫治疗是目前除手术、化疗、放疗及靶向治疗外,另一种能够有效改善肺癌预后的治疗方法。在各种免疫治疗方法中,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)在近年来发展迅速,已成为肿瘤治疗领域的新兴疗法及研究热点。其中,程序性死亡受体1(programmed death receptor 1,PD 1)及其配体程序性死亡配体 1(programmed death receptor ligand1,PD L1)的抑制剂在多种恶性肿瘤的治疗中均取得了显著疗效,部分药物已被美国FDA批准应用于临床。该文对PD 1／PD L1抑制剂在晚期非小细胞肺癌(non small cell lung cancer,NSCLC)患者治疗中的临床研究现状进行综述,探讨其在晚期NSCLC治疗中的临床应用价值、前景及面临的问题与挑战。     

免疫检查点抑制剂疗效相关预测模型的研究进展

免疫检查点抑制剂（immune checkpoint inhibitor,ICI）的应用让肿瘤治疗取得了新突破,但不同患者接受免疫治疗后疗效差异较大,仅部分患者能够从中获益。通过检测一些生物标志物可以预测ICI的疗效,如程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)及肿瘤突变负荷（tumor mutation burden,TMB）等。除此之外,目前已有多项研究基于肿瘤患者的基因组学、转录组学或影像组学等数据,筛选多个生物标志物并建立免疫治疗效果相关预测模型。这类模型具备严谨的建立及验证流程,能够纳入更多肿瘤免疫相关变量,有助于提高对ICI疗效的预测能力。本文就肿瘤免疫治疗效果相关预测模型进行综述,以期为免疫治疗获益人群的筛选提供新思路。     

非小细胞肺癌免疫检查点抑制剂治疗相关外周血生物标志物研究进展

以免疫检查点抑制剂(immune checkpoint inhibitors,ICI)为代表的免疫治疗改变了非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗模式,标志物指导下的免疫治疗是精准治疗的关键.基于组织的程序性死亡受体配体1(programmed cell death li...     

PD-1/PD-L1抑制剂的剂量选择与优化

肿瘤免疫治疗中,以程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡受体—配体1(programmed cell death-ligand 1,PD-L1)抑制剂为代表的免疫检查点单抗阻断治疗已逐渐成为肿瘤治疗领域的焦点.合理用药是使患者达到有效临床获益的重要环节,...     

卡瑞利珠单抗致免疫相关性肠炎1例并文献复习

<正>免疫检查点抑制剂(immune checkpoint inhibitor,ICI)^[1]是目前临床应用广泛的抗肿瘤药物,包括细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte antigen 4,CTLA-4)抗体、细胞程序性死亡受体1(programmed cell death receptor 1,PD-1)抗体及程序性死亡配体1(programmed death-ligand1,PD-L1)抗体这几种制剂。随着ICI的广泛使用,越来越多累及皮肤、内分泌、肝脏等的免疫相关性不良反应(immune-related adverse effects,irAEs)^[2-3]被报道,     

免疫检查点抑制剂治疗转移性胃癌疗效预测因子

近年来,免疫治疗被更加频繁地用于化疗后进展的转移性胃癌,其中使用最多的是免疫检查点抑制剂(ICI)。然而ICI在不同患者中的疗效差别较大,所以越来越多地开展了关于预测ICI疗效的生物标志物的研究。微卫星不稳定及EB病毒亚型是目前预测ICI治疗反应率相对确切的生物标志物;程序性死亡配体1及肿瘤突变负荷的预测作用仍存在争议...     

基于PD-1/PD-L1 抑制剂的肺癌免疫治疗预测标志物的研究进展

[摘要] 近年来,免疫检查点抑制剂在肺癌治疗中取得突破性进展,正迅速改变着肺癌的治疗模式,也标志着免疫治疗2.0 时代的到来。新的肿瘤治疗模式对精准医学提出更高要求,对程序性死亡受体1（programmed death 1, PD-1）/程序性死亡配体1（programmed death ligand 1, PD-L1）抑制剂预后生物标志物也在不断地探索之中,主要包括以下几个方面：PD-L1 表达水平、肿瘤基因组异质性与肿瘤新抗原、T细胞特点、肿瘤微环境以及机体整体状态等。本文将针对目前PD-1/PD-L1 抑制剂在肺癌免疫治疗中的潜在生物标志物最新临床研究进展及其研究前景进行综述。     

晚期胃癌一线免疫治疗的现状与进展

晚期胃癌预后较差,传统化疗疗效有限,未能满足患者治疗需求。免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）已改变晚期胃癌治疗格局,其中程序性死亡受体-1(programmed death-1,PD-1)抑制剂联合化疗、PD-1抑制剂联合曲妥珠单抗及化疗已分别成为人表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)阴性或阳性晚期胃癌一线治疗选择,其他免疫检查点分子抑制剂和癌症疫苗、过继性细胞输注等疗法的研究均在进行中。如何通过生物标志物筛选免疫治疗最佳获益人群,是近期研究热点。除肿瘤突变负荷、程序性死亡配体-1(programmed death-ligand 1,PD-L1)表达、微卫星不稳定性等,新兴标志物如循环肿瘤DNA、肠道微生物组学和细胞因子等均值得关注。本文就晚期胃癌一线免疫治疗的临床研究进展及展望进行综述。     

双免疫检查点抑制剂联合治疗在非小细胞肺癌中的研究进展

近年来,免疫检查点抑制剂广泛应用使得包括非小细胞肺癌(non-small cell lung cancer,NSCLC)在内的多种实体肿瘤的治疗模式发生了巨大变革,免疫检查点抑制剂(immune checkpoint inhibitor,ICI)在肿瘤治疗中的作用日益凸显,包括程序性死亡受体1(programmed cell death 1,PD-1)、程序性死亡配体1(programmed cell death ligand 1,PD-L1)、细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte-associated protein 4,CTLA-4)抗体在内的免疫药物,可以阻断效应T细胞上癌症来源的抑制信号,从而有效的清除残余的癌细胞及微小病灶,预防肿瘤的复发和转移。为了使更多患者受益,正在研究双免疫联合的治疗策略。本文旨在对双免疫联合治疗的机制、联合治疗模式、有效性及安全性进行综述。     

晚期胃癌免疫检查点抑制剂治疗的临床研究进展

[摘要] 晚期胃癌治疗方法有限,预后较差。2017 年,针对程序性死亡蛋白-1（programmed cell death protein-1, PD-1）和程序性死亡配体-1（programmed death ligand-1, PD-L1）的免疫检查点抑制剂获批用于晚期胃癌治疗,提示胃癌免疫治疗时代已经到来。然而,相对于肺癌,免疫检查点抑制剂尚未获批用于胃癌一、二线治疗。目前,大量胃癌免疫治疗临床试验正在进行中,其模式还在进一步优化,包括免疫联合化疗、免疫检查点抑制剂联合其他免疫治疗及新型免疫检查点抑制剂的应用等,同时寻找合适的肿瘤标志物,筛选优势人群用于胃癌精准免疫治疗。本文着重讨论晚期胃癌免疫检查点抑制剂治疗的临床研究最新进展。     

Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.     

Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies.The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti–programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents.The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies.In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.     

PD-1/PD-L1抑制剂在尿路上皮癌治疗中的研究进展

近年来,随着人们对肿瘤免疫生物学认识的不断深入,针对免疫检查点抑制的系统免疫疗法在尿路上皮癌领域得到了广泛的探索和临床应用。程序性细胞死亡受体1(programmed death 1,PD-1)及其配体(programmed death ligand 1,PD-L1)是机体免疫活性的重要负性调节因子,可防止正常组织和自身免疫功能的破坏。迄今为止,美国食品和药物管理局(Food and Drug Administration,FDA)已批准了可阻断PD-1(Pembrolizumab和Nivolumab)或PD-L1(Atezolizumab、Durvalumab和Avelumab)的五种免疫检查点抑制剂,根据在相关临床试验中观察到的持久的治疗反应和可控的安全性,用于局部晚期或转移性尿路上皮癌的一线或二线治疗。本文就PD-1/PD-L1抑制剂在尿路上皮癌中的研究进展作一综述。     

免疫检查点抑制剂治疗结直肠癌生物标志物的研究进展

免疫检查点抑制剂（immune checkpoint inhibitors，ICI）在多种晚期实体瘤治疗中取得了较好的临床疗效，其中包括结直肠癌。但是大多数的肿瘤患者对ICI的客观反应率（objective response rate，ORR）不理想，易发生治疗耐药性，甚至出现超进展现象。寻找预测免疫治疗疗效的生物标志物，筛选出合适的人群至关重要。目前有多种生物标志物在预测ICI治疗结直肠癌疗效显示出指导价值，但最优的标志物仍未确定，需要进一步的大规模前瞻性研究证实潜在标志物的价值。本文将对免疫检查点抑制剂治疗结直肠癌的正性和负性生物标志物的研究进展进行综述。      

The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB-high vs. TMB-low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD-L1) expression does not show a difference between female and male, suggesting TMB, but not PD-L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients.     

Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy

Gastric Cancer - Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death...     

非小细胞肺癌免疫治疗疗效预测的研究进展

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)治疗晚期非小细胞肺癌进入了一个新纪元,但不同于靶向治疗,免疫治疗没有明确的疗效预测因子以指导临床。目前应用较多的是程序性死亡受体配体(programmed cell death ligand 1,PD-L1)表达的检测,然而多项临床试验结果提示只有约20%的NSCLC患者能从中获益。而肿瘤突变负荷(tumor mutation burden,TMB)也逐渐兴起,还有许多检测因子尚在发现中。本综述旨在探讨非小细胞肺癌中免疫治疗的疗效预测因子以更好地指导临床。     

非小细胞肺癌免疫治疗研究进展

近年来,肺癌的治疗手段层出不穷,从传统化疗到靶向药物,再到免疫检查点抑制剂的出现,很大程度上改善了患者的预后,延长了患者生存期。免疫检查点抑制剂的应用,即免疫治疗,一改传统的治疗方式,作用于程序性细胞死亡蛋白-1（PD-1）及其配体（PD-L1）发挥有效且持久的抗肿瘤反应。本文主要介绍了近年来免疫治疗一线、二线应用于非小细胞肺癌（NSCLC）的研究情况,影响免疫治疗疗效的因素,及免疫治疗的相关毒副反应。